Fourier Transform (FT) nuclear magnetic resonance (NMR) spectroscopy (Ernst et al., Principles of Nuclear Magnetic Resonance in One and Two Dimensions, Oxford Univ. Press: Oxford (1987)) is one of the most widely used analytical tools in science and engineering (Jacobsen, NMR Spectroscopy Explained; Wiley: New York (2007)). FT NMR experiments rely on acquiring ‘free induction decays’ (FIDs) which, after FT, yield the desired frequency domain spectra. Quite generally, more than a single FID has to be recorded for a given NMR experiment in order to suppress spectral artifacts and/or to implement multi-dimensional data acquisition based on sampling of indirect evolution time periods and coherence pathway selection. Particularly when considering the unprecedented sensitivity of spectrometers equipped with cryogenic probes, one nowadays routinely faces the situation that the NMR experiment time is dictated by the number of FIDs required to record a distinct type of spectrum (with sufficient resolution in indirect dimensions), and not by sensitivity limitations which require signal averaging beyond the need for radio-frequency phase cycling and indirect time domain sampling. (Szyperski et al., Proc. Natl. Acad. Sci. U.S.A., 99:8009-8014 (2002)). To best capitalize on costly NMR hardware, one evidently prefers ‘sensitivity limited’ data acquisition (Szyperski et al., Proc. Natl. Acad. Sci. U.S.A., 99:8009-8014 (2002)) in which the number of FIDs, i.e., the measurement time, is chosen such that the resulting signal-to-noise (S/N) ratios are adjusted to a level ensuring reliable data interpretation while avoiding unnecessarily high S/N ratios.
NMR approaches were thus developed to accelerate NMR data acquisition (Atreya et al., Methods Enzymol., 394:78-108 (2005)). Many innovations emerged in the field of biological NMR spectroscopy (Cavanagh et al., Protein NMR Spectroscopy, Academic Press: San Diego (2007)) where stable isotope (13C/15N) labeled biological macromolecules are studied. The isotope labeling enables one to efficiently record three-dimensional (3D) or four-dimensional (4D) 13C/15N-resolved spectra. In turn, the high spectral dimensionality implies high sampling demand and long minimal measurement times, which creates an urgent demand for rapid data acquisition techniques. Widely used biological NMR techniques include: (i) Reduced-dimensionality (RD) NMR (Szyperski et al., J. Am. Chem. Soc., 115:9307-9308 (1993); Brutscher et al., J. Magn. Reson. Ser. B, 105:77-82 (1994); Szyperski et al., J. Biomol. NMR, 11:387-405 (1998); Szyperski et al., Proc. Natl. Acad. Sci. U.S.A., 99:8009-8014 (2002)), (ii) its generalization, G-matrix FT (GFT) projection NMR (Kim et al., J. Am. Chem. Soc., 125:1385-1393 (2003); Atreya et al., Proc. Natl. Acad. Sci. U.S.A., 101:9642-9647 (2004); Kim et al., J. Biomol. NMR, 28:117-130 (2004); Xia et al., J. Biomol. NMR, 29:467-474 (2004); Atreya et al., J. Am. Chem. Soc., 127:4554-4555 (2005); Eletsky et al., J. Am. Chem. Soc., 127:14578-14579 (2005); Yang et al., J. Am. Chem. Soc., 127:9085-9099 (2005); Szyperski et al., Magn. Reson. Chem., 44:51-60 (2006); Atreya et al., J. Am. Chem. Soc., 129:680-692 (2007); Xia et al., J. Magn. Resoni., 190:142-148 (2008)) and the techniques PR NMR (Kupce et al., J. Am. Chem. Soc., 126:6429-40 (2004)), APSY (Hiller et al., Proc. Natl. Acad. Sci. U.S.A., 102:10876-10881 (2005)), and Hi-Fi NMR (Eghbalnia et al., J. Am. Chem. Soc., 127: 12528-12536 (2005)) which are based on GFT NMR data collection, and (iii) Covariance NMR spectroscopy (Bruschweiler, J. Chem. Phys., 121:409-414 (2004); Bruschweiler et al., J. Chem. Phys., 120:5253-5260 (2004); Zhang et al., J. Am. Chem. Soc., 126:13180-13181 (2004); Chen et al., J. Am. Chem. Soc., 128:15564-15565 (2006)). Longitudinal relaxation optimization (Pervushin et al., J. Am. Chem. Soc., 124:12898-12902 (2002); Deschamps et al., J. Magn. Reson., 178:206-211 (2006)) can further accelerate data acquisition for experiments based on initial excitation and detection of polypeptide backbone amide proton (Atreya et al., Proc. Natl. Acad. Sci. U.S.A., 101:9642-9647 (2004); Schanda et al., J. Am. Chem. Soc., 128:9042-9043 (2006); Gal et al., J. Am. Chem. Soc., 129:1372-1377 (2007)) or aromatic proton magnetization (Eletsky et al., J. Am. Chem. Soc., 127:14578-14579 (2005)). Valuable other approaches were developed and thus far primarily applied for smaller molecules, e.g. Hadamard NMR spectroscopy (Bircher et al., J. Magn. Reson., 89:146-152 (1990); Blechta et al., Chem. Phys. Lett., 215:341-346 (1993)) and Ultrafast NMR (Frydman et al., Proc. Natl. Acad. Sci. U.S.A., 99:15858-15862 (2002); Frydman et al., J. Am. Chem. Soc., 125:9204-9217 (2003); Shrot et al., J. Chem. Phys., 125:204507(1-12) (2006); Mishkovsky et al., J. Biomol. NMR, 39:291-301 (2007)).
Ultrafast NMR is the only technique that allows one to record multidimensional spectra with a single scan. It is based on (i) spatiotemporal encoding of indirect chemical shift evolution followed by (ii) repetitive decoding and re-encoding during evolution of chemical shifts in the direct dimension. Step (i) requires the application of a train of spatially selective excitation pulses, each consisting of a shaped radiofrequency pulse in conjunction with a pulsed field gradient (PFG). This ensures that only a fraction of the sample, for example, a ‘section’ is excited. Step (ii) is based on the employment of a train of PFGs with alternating signs (‘readout PFGs’) during signal detection, which poses high demands on the spectrometer hardware. Even if the significant loss of sensitivity associated with the application of readout PFGs can be reduced using a single readout PFG of constant strength (Shrot et al., J. Chem. Phys., 125:204507(1-12) (2006)), the requirement to incorporate these PFGs represents a major limitation of Ultrafast NMR.
In another vein, Loening et al. (Loening et al., J. Magn. Reson., 164:321-328 (2003)) and Bhattacharyya and Kumar (Bhattacharyya et al., Chem. Phys. Lett., 383:99-103 (2004)) have employed spatially selective excitation to speed up nuclear spin relaxation measurements. In these experiments, separation of signals arising from spatially different parts of the sample is accomplished either by ‘time-staggered’ acquisition or by use of readout PFGs. Spatially selective excitation has also been applied to high resolution NMR for the suppression of zero-quantum coherence (Thrippleton et al., Angew. Chem. Intl. Ed. Engl., 42:3938-3941 (2003); Cano et al., J. Magn. Reson., 167:291-297 (2004)).
For a large number of widely used, often 2D [1H,1H] NMR experiments, it is the cycling of radiofrequency pulse phases or radiofrequency pulse flip-angles for coherence selection and/or artifact suppression (Ernst et al., Principles of Nuclear Magnetic Resonance in One and Two Dimensions, Oxford Univ. Press, Oxford (1987)) which dictates, besides the sampling of indirect evolution periods, minimal measurement times: an n-step cycle implies that (at least) n FIDs have to be acquired and added.
Consequently, there is a genuine need for methods which allow a phase, flip angle, or pulsed field gradient strength cycle to be performed simultaneously rather than sequentially. The present invention is directed to overcoming these and other deficiencies in the art.